Abstract WP378: NOTCH3 mutation does not affect cerebral collateral arteriogenesis and cerebrovascular reserve after unilateral common carotid artery occlusion in mice

Collateral arteriogenesis plays an important role in maintaining cerebral blood flow (CBF) in patients with critical stenosis or occlusion of major cerebral arteries. A large variation exists among individuals in both the extent of native collaterals and the capacity for arteriogenesis in response to arterial obstruction. Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic inherited form of small vessel disease, characterized by the accumulation of NOTCH3 extracellular domain around small caliber arteries. Here, we investigated the influences of genetic background and the NOTCH3 mutation on collateral arteriogenesis and the restoration of cerebral reserve. We used 115 male and 98 female mice from three strains (C57BL/6J, FVB/NJ, BALB/cJ) and two age groups (young: 20±4 weeks; aged: 69±20 weeks). The right common carotid artery was permanently occluded (RCCAO) via suture ligation, compared with shams. The diameters of the circle of Willis (COW) arteries and pial collaterals were assessed 4 weeks after RCCAO. Resting CBF and CBF reserve during induced hypotension were evaluated using laser speckle flowmetry (LSF) at 3 hours and 4 weeks after RCCAO. Regions of interest were placed on both hemispheres in the major arterial territories and watersheds. In young C57 and FVB (R169C WT) mice, RCCAO led to a significant increase in the diameters of the right posterior communicating artery (PCommA), to a lesser extent, the bilateral anterior cerebral arteries, and pial collaterals bilaterally. In contrast, young BALB mice showed that the right PCommA and pial collateral growth were diminished after RCCAO. In young R169C mutant mice, the COW arteriogenesis was comparable to that in WT mice, while pial collateral growth was reduced after RCCAO. In both aged WT and R169C mice, the COW arteriogenesis was preserved and more prominent in R169C mice, whereas pial collateral growth was diminished in both genotypes. LSF revealed a reduction in CBF upon acute RCCAO in both young WT and R169C mice. Baseline CBF recovered but cerebrovascular reserve appeared mildly reduced during hypotension four weeks after RCCAO, to a similar degree in both genotypes. In conclusion, our study reveals that collateral arteriogenesis after RCCAO is strain-dependent, and NOTCH3 mutation does not significantly impact intracranial large-vessel collateral arteriogenesis and cerebrovascular reserve after RCCAO.